Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep

Authors:

Charles A. Huard, Xueqin Gao, Maria E. Dey Hazra, Rony-Orijit Dey Hazra, Kimberly Lebsock, Jeremiah T. Easley, Peter J. Millett, and Johnny Huard

Abstract:

Fisetin has been shown to be beneficial for brain injury and age-related brain disease via different mechanisms. The purpose of this study was to determine the presence of senescent cells and the effects of fisetin on cellular senescence in the brain and other vital organs in old sheep, a more translational model. Female sheep 6–7 years old (N = 6) were treated with 100 mg/kg fisetin or vehicle alone on two consecutive days a week for 8 weeks. All vital organs were harvested at the time of sacrifice. Histology, immunofluorescence staining, and RT-Q-PCR were performed on different regions of brain tissues and other organs. Our results indicated that fisetin treatment at the current regimen did not affect the general morphology of the brain. The presence of senescent cells in both the cerebral brain cortex and cerebellum and non-Cornu Ammonis (CA) area of the hippocampus was detected by senescent-associated β-galactosidase (SA-β-Gal) staining and GL13 (lipofuscin) staining. The senescent cells detected were mainly neurons in both gray and white matter of either the cerebral brain cortex, cerebellum, or non-CA area of the hippocampus. Very few senescent cells were detected in the neurons of the CA1-4 area of the hippocampus, as revealed by GL13 staining and GLB1 colocalization with NEUN. Fisetin treatment significantly decreased the number of SA-β-Gal+ cells in brain cortex white matter and GL13+ cells in the non-CA area of the hippocampus, and showed a decreasing trend of SA-β-Gal+ cells in the gray matter of both the cerebral brain cortex and cerebellum. Furthermore, fisetin treatment significantly decreased P16+ and GLB1+ cells in neuronal nuclear protein (NEUN)+ neurons, glial fibrillary acidic protein (GFAP)+ astrocytes, and ionized calcium binding adaptor molecule 1 (IBA1)+ microglia cells in both gray and white matter of cerebral brain cortex. Fisetin treatment significantly decreased GLB1+ cells in microglia cells, astrocytes, and NEUN+ neurons in the non-CA area of the hippocampus. Fisetin treatment significantly decreased plasma S100B. At the mRNA level, fisetin significantly downregulated GLB1 in the liver, showed a decreasing trend in GLB1 in the lung, heart, and spleen tissues, and significantly decreased P21 expression in the liver and lung. Fisetin treatment significantly decreased TREM2 in the lung tissues and showed a trend of downregulation in the liver, spleen, and heart. A significant decrease in NRLP3 in the liver was observed after fisetin treatment. Finally, fisetin treatment significantly downregulated SOD1 in the liver and spleen while upregulating CAT in the spleen. In conclusion, we found that senescent cells were widely present in the cerebral brain cortex and cerebellum and non-CA area of the hippocampus of old sheep. Fisetin treatment significantly decreased senescent neurons, astrocytes, and microglia in both gray and white matter of the cerebral brain cortex and non-CA area of the hippocampus. In addition, fisetin treatment decreased senescent gene expressions and inflammasomes in other organs, such as the lung and the liver. Fisetin treatment represents a promising therapeutic strategy for age-related diseases.

For the complete study: Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep

Peter Millett, MD

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Alexandra Thompson

Mar 23, 2024

by Alexandra Thompson on Peter Millett, MD

110%

Dr. Millett and his team did a SLAP tear repair and bicep tenodesis on my left shoulder. I use my arms as an artist, and love to swim in the ocean, surf, paddle, and telemark ski. So regaining full use of my shoulder and keeping my bicep attached was very important to me. Now, over two years later, my shoulder has the equivalent range of motion as my other arm and as before the injury, and no pain. After the first three months it felt so good and was so strong that - to my horror - I completely forgot my six-month follow-up.

Not only did Dr. Millett and his team make my arm as good as new, but having had the experience of such kindness and expertise throughout the process of surgery and recovery is like an added shoulder superpower.

Thank you Rita, Brooke, Jason, Sarah, Camille, Olivia, Dr. Millett and everyone! And see you soon when my husband comes in for his knee...

Jeff Chandler

Jan 31, 2022

by Jeff Chandler on Peter Millett, MD

Flawless procedure, Easy recovery

Dr. Millet's repaired my knee and tibia, following a botched operation by a different surgeon. That procedure was virtually pain free and I was weight bearing within a few days. That was 18 years ago and the knee is still strong. A few years after the knee incident, Dr Millet repaired my shoulder. My insurance company approved me for 3 months of disability following that surgery. I was off pain medication in 2 days and had 90% range of motion within a week. I withdrew my disability claim and returned to work within two weeks of surgery. I’m not a famous athlete—just a regular guy. Nonetheless, I was treated like an NFL at the Steadman clinic. Most notable was the time for recovery. Other surgeons perform their hour-long task in the OR and don’t involve themselves in the other functions. Peter and his team manages the entire process from diagnosis, anesthesia, nursing care, and therapy. He takes a holistic approach to patient care and doesn’t skip any steps.

Jenn West

Jul 2, 2021

by Jenn West on Peter Millett, MD

Saved My Life

I went to Dr. Millett after 7 knee surgeries (6 on my right and 1 on my left) and had seen 11 different surgeons who all refused to remove femur metal from my right leg. I am highly allergic to metal and the chronic pain was leaving me bedridden for 3.5wks out of a month. He personally wrote me back on my inquiry, listened to my concerns, scheduled my surgery within a week (due to insurance issues) and personally followed up with my recovery. The level of patient care from Dr. Millett and his ENTIRE team is above any care I have ever received in my 20 years of dealing with orthopedic surgeons. There are not enough words to describe the level of care, dedication and professionalism you receive from Dr. Millett and his staff.
My only disappointment is that I did not find him sooner!!!

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Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep

Authors:

Abstract:

About the Author: Peter Millett, MD